tbuckley/cabot-search huggingface dataset:
Association of Remdesivir Treatment With Mortality Among Hospitalized Adults With COVID-19 in the United States
Authors: Anand P. Chokkalingam, Jennifer Hayden, Jason D. Goldman, Hu Li, Julius Asubonteng, Essy Mozaffari, Christopher Bush, Jocelyn R. Wang, Amanda Kong, Anu O. Osinusi, Robert L. Gottlieb
Journal: JAMA Network Open (2022)

SARS-CoV-2, which causes COVID-19, poses considerable morbidity and mortality risks. Studies using data collected during routine clinical practice can supplement randomized clinical trials to provide needed evidence, especially during a global pandemic, and can yield markedly larger sample sizes to assess outcomes for important patient subgroups.
Bayesian Estimation of Human Population Toxicokinetics of PFOA, PFOS, PFHxS, and PFNA from Studies of Contaminated Drinking Water
Authors: Weihsueh A. Chiu, Meghan T. Lynch, Claire R. Lay, Adriana Antezana, Parker Malek, Sara Sokolinski, Rachel D. Rogers
Journal: Environmental Health Perspectives (2022)

Background: Setting health-protective standards for poly- and perfluoroalkyl substances (PFAS) exposure requires estimates of their population toxicokinetics, but existing studies have reported widely varying PFAS half-lives (T½) and volumes of distribution (Vd). Objectives: We combined data from multiple studies to develop harmonized estimates of T½ and Vd, along with their interindividual variability, for four PFAS commonly found in drinking water: perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS). Methods: We identified published data on PFAS concentrations in human serum with corresponding drinking water measurements, separated into training and testing data sets. We fit training data sets to a one-compartment model incorporating interindividual variability, time-dependent drinking water concentrations, and background exposures. Use of a hierarchical Bayesian approach allowed us to incorporate informative priors at the population level, as well as at the study level. We compared posterior predictions to testing data sets to evaluate model performance. Results: Posterior median (95% CI) estimates of T½ (in years) for the population geometric mean were 3.14 (2.69, 3.73) for PFOA, 3.36 (2.52, 4.42) for PFOS, 2.35 (1.65, 3.16) for PFNA, and 8.30 (5.38, 13.5) for PFHxS, all of which were within the range of previously published values. The extensive individual-level data for PFOA allowed accurate estimation of population variability, with a population geometric standard deviation of 1.57 (95% CI: 1.42, 1.73); data from other PFAS were also consistent with this degree of population variability. Vd estimates ranged from 0.19 to 0.43L/kg across the four PFAS, which tended to be slightly higher than previously published estimates. Discussion: These results have direct application in both risk assessment (quantitative interspecies extrapolation and uncertainty factors for interindividual variability) and risk communication (interpretation of monitoring data). In addition, this study provides a rigorous methodology for further refinement with additional data, as well as application to other PFAS. https://doi.org/10.1289/EHP10103
Educational Attainment and Childhood-Onset Type 1 Diabetes
Authors: Robert French, Dylan Kneale, Justin T. Warner, Holly Robinson, James Rafferty, Adrian Sayers, Peter Taylor, John W. Gregory, Colin M. Dayan
Journal: Diabetes Care (2022)

To quantify associations of educational outcomes with type 1 diabetes status and glycemic management (HbA1c).This was a record linkage study of schools and higher (college) education data sets linked to national diabetes audits. The population includes all Welsh children attending school between 2009 and 2016, yielding eight academic cohorts with attainment data, including 263,426 children without diabetes and 1,212 children diagnosed with type 1 diabetes. Outcomes include standardized educational attainment for those aged 16 years, higher education participation for those aged ≥18 years, and school absences among those aged 6-16 years.Comparison between children with type 1 diabetes and children without diabetes showed no strong evidence of associations for student attainment (0.001 SD, 95% CI -0.047 to 0.049, P < 0.96, n = 1,212 vs. 263,426) or higher education entry rates (odds ratio 1.067, 95% CI 0.919-1.239, P < 0.39, n = 965 vs. 217,191), despite nine more sessions of absence from school annually (P < 0.0001). However, attainment in children in the most optimal HbA1c quintile was substantially better than for children without diabetes (0.267 SD, 95% CI 0.160-0.374, P < 0.001) while being worse than for children without diabetes in the least optimal quintile (-0.395 SD, 95% CI -0.504 to -0.287, P < 0.001). Attainment did not differ by duration of "exposure" to diabetes based on age at diagnosis.Despite more school absences, diabetes diagnosis is not associated with educational attainment or entry into higher education, although attainment does vary by HbA1c level, which may be explained in part (or wholly) by unobserved shared personal, family, or socioeconomic characteristics associated with both success in education and effective glycemic self-management.
Sex, Racial, and Ethnic Representation in COVID-19 Clinical Trials
Authors: Hong Xiao, Riha Vaidya, Fang Liu, Ximing Chang, Xiaoqian Xia, Joseph M. Unger
Journal: JAMA Internal Medicine (2022)

Since the onset of the COVID-19 pandemic, there have been calls for COVID-19 clinical trials to be fully representative of all demographic groups. However, limited evidence is available about the sex, racial, and ethnic representation among COVID-19 prevention and treatment trials.To investigate whether female participants and racial and ethnic minority individuals are adequately represented in COVID-19 prevention and treatment trials in the US.Identified studies were registered on ClinicalTrials.gov or published in the PubMed database from October 2019 to February 2022.Included studies must have provided the number of enrolled participants by sex, race, or ethnicity. Only interventional studies conducted in the US for the primary purpose of the diagnosis, prevention, or treatment of (or supportive care for) COVID-19 conditions were included.Data on counts of enrollments by demographic variables (sex, race, and ethnicity) and location (country and state) were abstracted. Studies were broadly categorized by primary purpose as prevention (including vaccine and diagnosis studies) vs treatment (including supportive care studies). A random effects model for single proportions was used. Trial estimates were compared with corresponding estimates of representation in the US population with COVID-19.Sex, racial, and ethnic representation in COVID-19 clinical trials compared with their representation in the US population with COVID-19.Overall, 122 US-based COVID-19 clinical trials comprising 176 654 participants were analyzed. Studies were predominantly randomized trials (n = 95) for treatment of COVID-19 (n = 103). Sex, race, and ethnicity were reported in 109 (89.3%), 95 (77.9%), and 87 (71.3%) trials, respectively. Estimated representation in prevention and treatment trials vs the US population with COVID-19 was 48.9% and 44.6% vs 52.4% for female participants; 23.0% and 36.6% vs 17.7% for Hispanic or Latino participants; 7.2% and 16.5% vs 14.1% for Black participants; 3.8% and 4.6% vs 3.7% for Asian participants; 0.2% and 0.9% vs 0.2% for Native Hawaiian or Other Pacific Islander participants; and 1.3% and 1.4% vs 1.1% for American Indian or Alaska Native participants. Compared with expected rates in the COVID-19 reference population, female participants were underrepresented in treatment trials (85.1% of expected; P < .001), Black participants (53.7% of expected; P = .003) and Asian participants (64.4% of expected; P = .003) were underrepresented in prevention trials, and Hispanic or Latino participants were overrepresented in treatment trials (206.8% of expected; P < .001).In this systematic review and meta-analysis, aggregate differences in representation for several demographic groups in COVID-19 prevention and treatment trials in the US were found. Strategies to better ensure diverse representation in COVID-19 studies are needed, especially for prevention trials.
Tocilizumab in Giant Cell Arteritis: Better Understanding the Benefits
Authors: Frank Buttgereit, Andriko Palmowski, Idil Esen, Elisabeth Brouwer
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
All Older Adults Benefit From Pneumococcal Vaccinations—The Case for Evaluating Vaccine Effectiveness Using All-Cause Pneumonia
Authors: Amber Hsiao, Nicola P. Klein
Journal: JAMA Internal Medicine (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Effectiveness of Goal-Directed and Outcome-Based Financial Incentives for Weight Loss in Primary Care Patients With Obesity Living in Socioeconomically Disadvantaged Neighborhoods
Authors: Joseph A. Ladapo, Stephanie L. Orstad, Soma Wali, Judith Wylie-Rosett, Chi-Hong Tseng, Un Young Rebecca Chung, Miguel A. Cuevas, Christina Hernandez, Susan Parraga, Robert Ponce, Victoria Sweat, Sandra Wittleder, Andrew B. Wallach, Suzanne B. Shu, Noah J. Goldstein, Isaac Dapkins, Melanie Jay
Journal: JAMA Internal Medicine (2022)

Financial incentives for weight management may increase use of evidence-based strategies while addressing obesity-related economic disparities in low-income populations.
Obstetric and Perinatal Outcomes of Singleton Births Following Single- vs Double-Embryo Transfer in Sweden
Authors: Kenny A. Rodriguez-Wallberg, Arturo Reyes Palomares, Hanna P. Nilsson, Anna Sara Oberg, Frida Lundberg
Journal: JAMA Pediatrics (2022)

Importance Pregnancies resulting from assisted reproductive technology are associated with an increased risk of adverse perinatal outcomes compared with those following natural conception. Previous studies have shown an association of pregnancies resulting from transfer of multiple embryos with these negative findings. Objective To determine the risk for adverse outcomes in singletons conceived through assisted reproduction using double-embryo transfer (DET) vs single-embryo transfer (SET). Design, Setting, and Participants This cohort study used data from women who achieved singleton deliveries after SET or DET in Sweden between 2007 and 2017 as recorded in the National Quality Registry for Assisted Reproduction. All embryo transfers, at cleavage or blastocyst stage, replaced in fresh or frozen treatment cycles were included. Data on obstetric and neonatal outcomes were retrieved by linkage to the National Medical Birth Register. Naturally conceived singletons were included as a reference group. Data were analyzed between September 2021 and August 2022. Exposures Double-embryo transfer leading to singleton birth. Main Outcomes and Measures Relative risk ratios or odds ratios (ORs) and absolute risk differences (ARDs) in percentage points with 95% CIs were calculated for obstetric and perinatal outcomes in singleton births conceived using DET vs SET. Results Among 1 115 863 singleton births, 30 713 singletons were born after SET and 5123 after DET. A higher risk of neonatal death was found in singletons after DET vs SET (OR, 2.67 [95% CI, 1.28-5.55]; ARD, 0.2 percentage points [95% CI, 0.0-0.4 percentage points]). In frozen embryo transfers, DET was associated with a higher risk of low birth weight (OR, 1.64 [95% CI, 1.19-2.25]; ARD, 2.0 percentage points [95% CI, 0.5-3.5 percentage points]). Among blastocyst transfers, DET was associated with very preterm birth (relative risk ratio, 2.64 [95% CI, 1.50-4.63]; ARD, 1.8 percentage points [95% CI, 0.3-3.4 percentage points]) and low birth weight (OR, 1.83 [95% CI, 1.29-2.60]; ARD, 3.2 percentage points [95% CI, 0.9-5.5 percentage points]). Conclusions and Relevance These results indicate a higher risk of adverse outcomes following DET, even when the result is a singleton birth, vs singletons born after SET. Adverse outcomes were mainly observed in singletons following DET using frozen embryos and blastocysts.
FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Jaleh Fallah, Sundeep Agrawal, Haley Gittleman, Mallorie H. Fiero, Sriram Subramaniam, Christy John, Wei Chen, Tiffany K. Ricks, Gang Niu, Anthony Fotenos, Min Wang, Kelly Chiang, William F. Pierce, Daniel L. Suzman, Shenghui Tang, Richard Pazdur, Laleh Amiri-Kordestani, Amna Ibrahim, Paul G. Kluetz
Journal: Clinical Cancer Research (2022)

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.
Dasatinib for treatment of CAR T-cell therapy-related complications
Authors: Katharina Baur, Dominik Heim, Astrid Beerlage, Anna S Poerings, Bastian Kopp, Michael Medinger, Jan C Dirks, Jakob R Passweg, Andreas Holbro
Journal: Journal for ImmunoTherapy of Cancer (2022)

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are severe, potentially life-threatening side effects of chimeric antigen receptor T-cell (CAR T) therapy caused by the release of cytokines by proliferating and activated CAR T-cells. Current mainstay treatment includes interleukin-1 and interleukin-6 (IL-6) blockade and steroids. The use of steroids is still controversial, since they may have the potential to irreversibly damage CAR T-cells and thus increase the risk of relapse. Therefore, additional treatment options need to be explored. We report the successful treatment of a patient with a grade 3 CRS and grade 4 ICANS refractory to IL-6 blockade and steroids with the tyrosine kinase inhibitor dasatinib. The use of dasatinib for treatment of CAR T-cell therapy-related severe complications warrants further studies.
ABC transporters affects tumor immune microenvironment to regulate cancer immunotherapy and multidrug resistance
Authors: Jingyi Fan, Kenneth Kin Wah To, Zhe-Sheng Chen, Liwu Fu
Journal: Drug Resistance Updates (2022)

Multidrug resistance (MDR) is the phenomenon in which cancer cells simultaneously develop resistance to a broad spectrum of structurally and mechanistically unrelated drugs. MDR severely hinders the effective treatment of cancer and is the major cause of chemotherapy failure. ATP-binding cassette (ABC) transporters are extensively expressed in various body tissues, and actively transport endogenous and exogenous substrates through biological membranes. Overexpression of ABC transporters is frequently observed in MDR cancer cells, which promotes efflux of chemotherapeutic drugs and reduces their intracellular accumulation. Increasing evidence suggests that ABC transporters regulate tumor immune microenvironment (TIME) by transporting various cytokines, thus controlling anti-tumor immunity and sensitivity to anticancer drugs. On the other hand, the expression of various ABC transporters is regulated by cytokines and other immune signaling molecules. Targeted inhibition of ABC transporter expression or function can enhance the efficacy of immune checkpoint inhibitors by promoting anticancer immune microenvironment. This review provides an update on the recent research progress in this field.
Intravital molecular imaging reveals that ROS-caspase-3-GSDME-induced cell punching enhances humoral immunotherapy targeting intracellular tumor antigens
Authors: Bolei Dai, Ren Zhang, Shuhong Qi, Lei Liu, Xian Zhang, Deqiang Deng, Jie Zhang, Yilun Xu, Fanxuan Liu, Zheng Liu, Qingming Luo, Zhihong Zhang
Journal: Theranostics (2022)

Tumor antigens (TAs)-induced humoral immune responses or TAs-specific antibodies have great application prospects for tumor therapy.However, more than half of TAs are intracellular antigens (intra-Ags) that are hardly recognized by antibodies.It is worthy to develop immunotherapeutic strategies for targeting intra-Ags.Methods: We used the far-red fluorescent protein tfRFP as an intracellular antigen to immunize mice and generated a liver metastasis model by injecting tfRFP-expressing B16 melanoma cells (tfRFP-B16) via the spleen.Intravital molecular imaging and atomic force microscopy were performed to visualize the formation of tfRFP antigen-antibody complexes (also known as immune complexes) and punched holes in cell membranes. Results:The results showed that the tfRFP-elicited immune responses inhibited the metastasis of tfRFP-expressing melanoma cells in the liver.In the circulating tfRFP-B16 tumor cells, elevated reactive oxygen species (ROS) induced slight caspase-3 activation, a probable key factor in the cleavage of gasdermin E (GSDME) proteins and punching of holes in the tumor cell membrane.Increased tumor cell membrane permeability led to the release of intra-Ag tfRFP and binding with anti-tfRFP antibodies.The formation of tfRFP antigen-antibody complexes on the membranes of tfRFP-B16 cells activated complement components to form membrane attack complexes to further destroy the cell membrane.Neutrophils were rapidly recruited, and F4/80 + macrophages phagocytized the dying tumor cells. Conclusion:The process of circulating tumor cell elimination in the tfRFP-immunized mice was triggered through the ROS-caspase-3-GSDME pathway to form intra-Ag-antibody immune complexes, which were involved in the activation of the complement system, as well as the recruitment of neutrophils and F4/80 + macrophages.An intra-Ag-elicited humoral immune response is a potent strategy for eliminating liver metastasis, which is unaffected by the liver immune tolerogenic status.
Epigenetic Rewiring Underlies<i>SMARCA4</i>-Dependent Maintenance of Progenitor State in Pediatric<i>H3K27M</i>Diffuse Midline Glioma
Authors: Mary Clare Beytagh, William A. Weiss
Journal: Cancer Discovery (2022)

Epigenetic reprogramming drives tumorigenesis in pediatric H3K27M diffuse midline glioma (DMG) by altering the canonical functions of chromatin remodeling complexes. These studies (i) identified BRG1 (encoded by SMARCA4), the catalytic subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex, as a novel dependency in pediatric H3K27M glioma; (ii) investigated the molecular mechanisms underlying the maintenance of the progenitor state; and (iii) demonstrated efficacy for BRG1 inhibitors.The authors identified the BRG1 ATPase as a dependency in pediatric H3K27M-mutant DMG. SOX10 recruits BRG1 to regulatory elements to drive progression. Pharmacologically targeting BRG1 reduced tumor volume and improved survival in vivo. Inhibiting BRG1 ATPase represents a potential therapeutic strategy for pediatric H3K27M DMG. See related article by Panditharatna et al., p. 2880 (5) See related article by Mo et al., p. 2906 (4) .
Regression towards the mean—a plea for civility in peer review
Authors: Rahul Tony Rao, Beth Bareham
Journal: BMJ (2022)

Peer review is integral to the ongoing publication of high quality research.In pursuit of this aim, reviewers are expected to provide constructive feedback that helps authors improve their manuscripts. 1All too often, however, peer reviewers fall into the trap of harsh criticism rather than critical evaluation.Common pitfalls include reviews that are overly negative or incredibly brief, give little acknowledgment of the strengths of the manuscript, and use an unfriendly or insulting tone
In Vivo <i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis
Authors: Marian Galovic, Adam Al-Diwani, Umesh Vivekananda, Matthew C. Walker, Sarosh R. Irani, Matthias J. Koepp
Journal: JAMA Neurology (2022)

This case-control study uses a radiotracer and positron emission tomography to assess N-methyl-d-aspartate receptor (NMDAR) density changes during recovery from NMDAR-antibody encephalitis.